Chronic Fatigue Syndrome: Washington

Pall ML, Bedient SA. · School of Molecular Biosciences, Washington State University, Pullman, Washington 99164-4234, USA. · Int Tinnitus J. · Pubmed #18229788 No free full text.

Abstract: Peripheral tinnitus is a good candidate for inclusion under the NO/ONOO cycle etiological mechanism, fitting each of the five principles of this mechanism. Cases of tinnitus are initiated by at least 11 short-term stressors increasing nitric oxide or other cycle mechanisms. Such cycle elements as N-methyl-D-aspartate activity; oxidative stress; nitric oxide; peroxynitrite; vanilloid activity; NF-kappaB activity; and intracellular calcium levels are all reported to be elevated in tinnitus. Tinnitus is comorbid with some putative NO/ONOO- cycle diseases. Most important, multiple agents that down-regulate NO/ONOO- cycle biochemistry are reported to be helpful in the treatment of tinnitus and related diseases. Previous studies suggested that NO/ONOO cycle diseases may be best treated with complex combinations of agents predicted to lower NO/ONOO- cycle biochemistry, and such combinations may be helpful in tinnitus treatment. Other inner-ear-related defects, such as acute or progressive hearing loss, vertigo, and dizziness, may also be NO/ONOO cycle diseases.

Mease P. · Seattle Rheumatology Associates, Washington 98104, USA. · J Rheumatol Suppl. · Pubmed #16078356 No free full text.

Abstract: Fibromyalgia syndrome (FM) is a common chronic pain condition that affects at least 2% of the adult population in the USA and other regions in the world where FM is studied. Prevalence rates in some regions have not been ascertained and may be influenced by differences in cultural norms regarding the definition and attribution of chronic pain states. Chronic, widespread pain is the defining feature of FM, but patients may also exhibit a range of other symptoms, including sleep disturbance, fatigue, irritable bowel syndrome, headache, and mood disorders. Although the etiology of FM is not completely understood, the syndrome is thought to arise from influencing factors such as stress, medical illness, and a variety of pain conditions in some, but not all patients, in conjunction with a variety of neurotransmitter and neuroendocrine disturbances. These include reduced levels of biogenic amines, increased concentrations of excitatory neurotransmitters, including substance P, and dysregulation of the hypothalamic-pituitary-adrenal axis. A unifying hypothesis is that FM results from sensitization of the central nervous system. Establishing diagnosis and evaluating effects of therapy in patients with FM may be difficult because of the multifaceted nature of the syndrome and overlap with other chronically painful conditions. Diagnostic criteria, originally developed for research purposes, have aided our understanding of this patient population in both research and clinical settings, but need further refinement as our knowledge about chronic widespread pain evolves. Outcome measures, borrowed from clinical research in pain, rheumatology, neurology, and psychiatry, are able to distinguish treatment response in specific symptom domains. Further work is necessary to validate these measures in FM. In addition, work is under way to develop composite response criteria, intended to address the multidimensional nature of this syndrome. A range of medical treatments, including antidepressants, opioids, nonsteroidal antiinflammatory drugs, sedatives, muscle relaxants, and antiepileptics, have been used to treat FM. Nonpharmaceutical treatment modalities, including exercise, physical therapy, massage, acupuncture, and cognitive behavioral therapy, can be helpful. Few of these approaches have been demonstrated to have clear-cut benefits in randomized controlled trials. However, there is now increased interest as more effective treatments are developed and our ability to accurately measure effect of treatment has improved. The multifaceted nature of FM suggests that multimodal individualized treatment programs may be necessary to achieve optimal outcomes in patients with this syndrome.

Richardson RD, Engel CC. · VA Puget Sound Healthcare System, Seattle, WA, USA. · Neurologist. · Pubmed #14720312 No free full text.

Abstract: BACKGROUND: Medically unexplained physical symptoms (MUPS) and related syndromes are common in medical care and the general population, are associated with extensive morbidity, and have a large impact on functioning. Much of medical practice emphasizes specific pharmacological and surgical intervention for discrete disease states. Medical science, with its emphasis on identifying etiologically meaningful diseases comprised of homogeneous groups of patients, has split MUPS into a number of diagnostic entities or syndromes, each with its own hypothesized pathogenesis. However, research suggests these syndromes may be more similar than different, sharing extensive phenomenological overlap and similar risk factors, treatments, associated morbidities, and prognoses. Examples of syndromes consisting of MUPS include chronic fatigue syndrome, fibromyalgia, multiple chemical sensitivities, somatoform disorders, and 'Gulf War Syndrome.' REVIEW SUMMARY: This paper is a narrative review of the increasing body of evidence suggesting that MUPS and related syndromes are common, disabling, and costly. It emphasizes that MUPS occur along a continuum of symptom count, severity, and duration and may be divided into acute, subacute (or recurrent), and chronic types. Predisposing, precipitating, and perpetuating factors influence the natural history of MUPS. CONCLUSIONS: Effective symptom management involves collaborative doctor-patient approaches for identification of problems based on a combination of medical importance and patient readiness to initiate behavioral change, negotiated treatment goals and outcomes, gradual physical activation and exercise prescription. Additionally, efforts should be made to teach and support active rather than passive coping with the symptoms.

Aaron LA, Buchwald D. · Department of Oral Medicine, University of Washington, 1959 NE Pacific Street, B316, P.O. Box 356370, Seattle, WA 98195-6370, USA. · Best Pract Res Clin Rheumatol. · Pubmed #12849712 No free full text.

Abstract: This chapter reviews our current knowledge on the presence of overlapping syndromes in one form of chronic diffuse pain, fibromyalgia. Patients with fibromyalgia often present with signs and symptoms of other unexplained clinical conditions, including chronic fatigue syndrome, irritable bowel syndrome, temporomandibular disorders, and multiple chemical sensitivities. The high prevalence, impact on function and opportunities for treatment underscore the need for clinicians and researchers to screen routinely for co-morbid unexplained clinical conditions among persons with fibromyalgia. We, therefore, describe a simple approach to screening for such conditions in accordance with published criteria. Interventions should directly address both fibromyalgia symptoms and co-morbid unexplained clinical conditions, as well as the multiple factors that propagate pain, fatigue and limitations in function.

Pearce PZ. · The Rockwood Clinic, 14408 East Sprague Street, Spokane, WA 99216, USA. · Curr Sports Med Rep. · Pubmed #12831711 No free full text.

Abstract: The overtraining syndrome is a chronic fatiguing illness that affects highly motivated endurance athletes. It is characterized by declining performance when maintaining a normal training program. The cause seems to be failure of adaptation within the neuroendocrine system, due to inadequate periods of rest. The onset is insidious and unfortunately, once it manifests, the only treatment is rest. This article discusses the known pathophysiology of overtraining, along with practical aspects of evaluation and treatment.

Afari N, Buchwald D. · Department of Psychiatry, University of Washington, Seattle, USA. · Am J Psychiatry. · Pubmed #12562565 links to  free full text

Abstract: OBJECTIVE: Chronic fatigue syndrome is an illness characterized by disabling fatigue of at least 6 months, accompanied by several other symptoms. This review summarizes the current state of knowledge about chronic fatigue syndrome. METHOD: The case definition, prevalence, clinical presentation, evaluation, and prognosis of chronic fatigue syndrome are discussed. Research on the pathophysiology and treatment of chronic fatigue syndrome is reviewed. RESULTS: Chronic fatigue syndrome is diagnosed on the basis of symptoms. Patients with chronic fatigue syndrome experience significant functional impairment. Pathophysiological abnormalities exist across many domains, suggesting that chronic fatigue syndrome is a heterogeneous condition of complex and multifactorial etiology. Evidence also is beginning to emerge that chronic fatigue syndrome may be familial. Although chronic fatigue syndrome has significant symptom overlap and comorbidity with psychiatric disorders, several lines of research suggest that the illness may be distinct from psychiatric disorders. Patients' perceptions, attributions, and coping skills, however, may help perpetuate the illness. Treatment for chronic fatigue syndrome is symptom-based and includes pharmacological and behavioral strategies. Cognitive behavior therapy and graded exercise can be effective in treating the fatigue and associated symptoms and disability. CONCLUSIONS: Chronic fatigue syndrome is unlikely to be caused or maintained by a single agent. Findings to date suggest that physiological and psychological factors work together to predispose an individual to the illness and to precipitate and perpetuate the illness. The assessment and treatment of chronic fatigue syndrome should be multidimensional and tailored to the needs of the individual patient.

Pall ML, Satterlee JD. · School of Molecular Biosciences, Washington State University, Pullman 99164-4660, USA. · Ann N Y Acad Sci. · Pubmed #12000033 No free full text.

Abstract: Various types of evidence implicate nitric oxide and an oxidant, possibly peroxynitrite, in MCS and chemical intolerance (CI). The positive feedback loops proposed earlier for CFS may explain the chronic nature of MCS (CI) as well as several of its other reported properties. These observations raise the possibility that this proposed elevated nitric oxide/peroxynitrite mechanism may be the mechanism of a new disease paradigm, answering the question raised by Miller earlier: "Are we on the threshold of a new theory of disease?"

Aaron LA, Buchwald D. · Department of Medicine, Division of Internal Medicine, Harborview Medical Center, 325 Ninth Avenue, Box 359780, Seattle, WA 98104, USA. · Ann Intern Med. · Pubmed #11346323 No free full text.

Abstract: PURPOSE: Unexplained clinical conditions share features, including symptoms (fatigue, pain), disability out of proportion to physical examination findings, inconsistent demonstration of laboratory abnormalities, and an association with "stress" and psychosocial factors. This literature review examines the nature and extent of the overlap among these unexplained clinical conditions and the limitations of previous research. DATA SOURCES: English-language articles were identified by a search of the MEDLINE database from 1966 to January 2001 by using individual syndromes and their hallmark symptoms as search terms. STUDY SELECTION: Studies that assessed patients with at least one unexplained clinical condition and that included information on symptoms, overlap with other unexplained clinical conditions, or physiologic markers. Conditions examined were the chronic fatigue syndrome, fibromyalgia, the irritable bowel syndrome, multiple chemical sensitivity, temporomandibular disorder, tension headache, interstitial cystitis, and the postconcussion syndrome. DATA EXTRACTION: Information on authorship, patient and control groups, eligibility criteria, case definitions, study methods, and major findings. DATA SYNTHESIS: Many similarities were apparent in case definition and symptoms, and the proportion of patients with one unexplained clinical condition meeting criteria for a second unexplained condition was striking. Tender points on physical examination and decreased pain threshold and tolerance were the most frequent and consistent objective findings. A major shortcoming of all proposed explanatory models is their inability to account for the occurrence of unexplained clinical conditions in many affected patients. CONCLUSIONS: Overlap between unexplained clinical conditions is substantial. Most studies are limited by methodologic problems, such as case definition and the selection and recruitment of case-patients and controls.

Aaron LA, Buchwald D. · Department of Medicine, Harborview Medical Center, 325 Ninth Avenue, Box 359780, Seattle, WA 98104, USA. · Curr Rheumatol Rep. · Pubmed #11286667 No free full text.

Abstract: Several unexplained clinical conditions frequently coexist with fibromyalgia; these include chronic fatigue syndrome, irritable bowel syndrome, temporomandibular disorder, tension and migraine headaches, and others. However, only recently have studies directly compared the physiological parameters of these conditions (eg, fibromyalgia vs irritable bowel syndrome) to elucidate underlying pathogenic mechanisms. This review summarizes data from comparative studies and discusses their implications for future research.

Mease PJ, Clauw DJ, Gendreau RM, Rao SG, Kranzler J, Chen W, Palmer RH. · Seattle Rheumatology Associates, 1101 Madison Street, Suite 1000, Seattle, WA 98104, USA. · J Rheumatol. · Pubmed #19132781 No free full text.

Abstract: OBJECTIVE: To evaluate the safety and efficacy of milnacipran, a dual norepinephrine and serotonin reuptake inhibitor, in the treatment of fibromyalgia (FM). METHODS: A 27-week, randomized, double-blind, multicenter study compared milnacipran 100 and 200 mg/day with placebo in the treatment of 888 patients with FM. Two composite responder definitions were used to classify each patient's individual response to therapy. "FM responders" concurrently satisfied response criteria for improvements in pain (visual analog scale 24-h morning recall), patient global impression of change (PGIC), and physical functioning (SF-36 Physical Component Summary); while "FM pain responders" concurrently satisfied response criteria for improvements in pain and PGIC. RESULTS: At the primary endpoint, after 3-month stable dose treatment, a significantly higher percentage of milnacipran-treated patients met criteria as FM responders versus placebo (milnacipran 200 mg/day, p = 0.017; milnacipran 100 mg/day, p = 0.028). A significantly higher percentage of patients treated with milnacipran 200 mg/day also met criteria as FM pain responders versus placebo (p = 0.032). Significant pain reductions were observed after Week 1 with both milnacipran doses. At 15 weeks, milnacipran 200 mg/day led to significant improvements over placebo in pain (realtime, daily and weekly recall; all measures, p < 0.05), PGIC (p < 0.001), fatigue (p = 0.016), cognition (p = 0.025), and multiple SF-36 domains. Milnacipran was safe and well tolerated by the majority of patients during 27 weeks of treatment; nausea and headache were the most common adverse events. CONCLUSION: Milnacipran is safe and effective for the treatment of multiple symptoms of FM.

Pall ML. · School of Molecular Biosciences, Washington State University, Pullman, WA 99164-4234, USA. · Med Hypotheses. · Pubmed #18667279 No free full text.

Abstract: Post-radiation syndrome is proposed to be chronic fatigue syndrome (CFS) or a chronic fatigue syndrome-like illness, initiated by exposure to ionizing radiation. This view is supported by the nitric oxide/peroxynitrite (NO/ONOO-) cycle mechanism, the putative etiologic mechanism for CFS and related illnesses. Ionizing radiation may initiate illness by increasing nitric oxide levels via increased activity of the transcription factor NF-kappaB and consequent increased synthesis of the inducible nitric oxide synthase. Two types of components of the nitric oxide/peroxynitrite cycle have been studied in post-radiation syndrome patients and shown to be elevated. The symptoms and signs of post-radiation syndrome and its chronicity are similar or identical to those of chronic fatigue syndrome and can be explained as being a consequence of nitric oxide/peroxynitrite cycle etiology. While the data available to test this view are limited, it provides for the first time a comprehensive explanation for post-radiation syndrome.

Schur E, Afari N, Goldberg J, Buchwald D, Sullivan PF. · 1 Department of Medicine, University of Washington School of Medicine, Seattle,Washington, USA. · Twin Res Hum Genet. · Pubmed #17903114 No free full text.

Abstract: Prolonged fatigue equal to or greater than 1 month duration and chronic fatigue equal to or greater than 6 months duration are both commonly seen in clinical practice, yet little is known about the etiology or epidemiology of either symptom. Chronic fatigue syndrome (CFS), while rarer, presents similar challenges in determining cause and epidemiology. Twin studies can be useful in elucidating genetic and environmental influences on fatigue and CFS. The goal of this article was to use biometrical structural equation twin modeling to examine genetic and environmental influences on fatigue, and to investigate whether these influences varied by gender. A total of 1042 monozygotic (MZ) twin pairs and 828 dizygotic (DZ) twin pairs who had completed the University of Washington Twin Registry survey were assessed for three fatigue-related variables: prolonged fatigue, chronic fatigue, and CFS. Structural equation twin modeling was used to determine the relative contributions of additive genetic effects, shared environmental effects, and individual-specific environmental effects to the 3 fatigue conditions. In women, tetrachoric correlations were similar for MZ and DZ pairs for prolonged and chronic fatigue, but not for CFS. In men, however, the correlations for prolonged and chronic fatigue were higher in MZ pairs than in DZ pairs. About half the variance for both prolonged and chronic fatigue in males was due to genetic effects, and half due to individual-specific environmental effects. For females, most variance was due to individual environmental effects.

Schur EA, Afari N, Furberg H, Olarte M, Goldberg J, Sullivan PF, Buchwald D. · Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA. · J Gen Intern Med. · Pubmed #17503107 links to  free full text

Abstract: BACKGROUND: Considerable overlap in symptoms and disease comorbidity has been noted among medically unexplained and psychiatric conditions seen in the primary care setting, such as chronic fatigue syndrome, low back pain, irritable bowel syndrome, chronic tension headache, fibromyalgia, temporomandibular joint disorder, major depression, panic attacks, and posttraumatic stress disorder. OBJECTIVE: To examine interrelationships among these 9 conditions. DESIGN: Using data from a cross-sectional survey, we described associations and used latent class analysis to investigate complex interrelationships. PARTICIPANTS: 3,982 twins from the University of Washington Twin Registry. MEASUREMENTS: Twins self-reported a doctor's diagnosis of the conditions. RESULTS: Comorbidity among these 9 conditions far exceeded chance expectations; 31 of 36 associations were significant. Latent class analysis yielded a 4-class solution. Class I (2% prevalence) had high frequencies of each of the 9 conditions. Class II (8% prevalence) had high proportions of multiple psychiatric diagnoses. Class III (17% prevalence) participants reported high proportions of depression, low back pain, and headache. Participants in class IV (73% prevalence) were generally healthy. Class I participants had the poorest markers of health status. CONCLUSIONS: These results support theories suggesting that medically unexplained conditions share a common etiology. Understanding patterns of comorbidity can help clinicians care for challenging patients.

Pall ML. · School of Molecular Biosciences, Washington State University, Pullman, WA 99164-4234, USA. · Med Hypotheses. · Pubmed #17448611 No free full text.

Abstract: Short-term stressors, capable of increasing nitric oxide levels, act to initiate cases of illnesses including chronic fatigue syndrome, multiple chemical sensitivity, fibromyalgia and posttraumatic stress disorder. These stressors, acting primarily through the nitric oxide product, peroxynitrite, are thought to initiate a complex vicious cycle mechanism, known as the NO/ONOO- cycle that is responsible for chronic illness. The complexity of the NO/ONOO- cycle raises the question as to whether the mechanism that switches on this cycle is this complex cycle itself or whether a simpler mechanism is the primary switch. It is proposed here that the switch involves a combination of two variable switches, the increase of nitric oxide synthase (NOS) activity and the partial uncoupling of the NOS activity, with uncoupling caused by a tetrahydrobiopterin (BH4) deficiency. NOS uncoupling causes the NOS enzymes to produce superoxide, the other precursor of peroxynitrite, in place of nitric oxide. Thus partial uncoupling will cause NOS proteins to act like peroxynitrite synthases, leading, in turn to increased NF-kappaB activity. Peroxynitrite is known to oxidize BH4, and consequently partial uncoupling may initiate a vicious cycle, propagating the partial uncoupling over time. The combination of high NOS activity and BH4 depletion will lead to a potential vicious cycle that may be expected to switch on the larger NO/ONOO- cycle, thus producing the symptoms and signs of chronic illness. The role of peroxynitrite in the NO/ONOO- cycle also implies that such uncoupling is part of the chronic phase cycle mechanism such that agents that lower uncoupling will be useful in treatment.

Ullrich PM, Afari N, Jacobsen C, Goldberg J, Buchwald D. · Department of Rehabilitation Medicine, University of Washington, Seattle, WA 98104, USA. · Pain Med. · Pubmed #17371408 No free full text.

Abstract: OBJECTIVE: Individuals with chronic fatigue syndrome (CFS) experience many pain symptoms. The present study examined whether pain and fatigue ratings and pain threshold and tolerance levels for cold pain differed between twins with CFS and their cotwins without CFS. DESIGN: Cotwin control design to assess cold pain sensitivity, pain, and fatigue in monozygotic twins discordant for CFS. PATIENTS AND SETTING: Fifteen monozygotic twin pairs discordant for CFS recruited from the volunteer Chronic Fatigue Twin Registry at the University of Washington. RESULTS: Although cold pain threshold and tolerance levels were slightly lower in twins with CFS than their cotwins without CFS, these differences failed to reach statistical significance. Subjective ratings of pain and fatigue at multiple time points during the experimental protocol among twins with CFS were significantly higher than ratings of pain (P = 0.003) and fatigue (P < 0.001) by their cotwins without CFS. CONCLUSIONS: These results, while preliminary, highlight the perceptual and cognitive components to the pain experience in CFS. Future studies should focus on examining the heritability of pain sensitivity and the underlying mechanisms involved in the perception of pain sensitivity in CFS.

Smith WR, White PD, Buchwald D. · Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA. · BMC Psychiatry. · Pubmed #17101056 links to  free full text

Abstract: BACKGROUND: Patients with chronic fatigue syndrome typically report high levels of physical activity before becoming ill. Few studies have examined premorbid and current activity levels in chronically fatigued patients. METHODS: In a case-control study, 33 patients with chronic, unexplained, disabling fatigue attending a university-based clinic specializing in fatigue were compared to 33 healthy, age- and sex-matched controls. Patients rated their activity levels before their illness and currently, using scales designed for this purpose. Controls reported their level of activity of 2 years previously and currently. Chi-square analyses, Student's t tests, and Wilcoxon signed rank tests were used in pair matched analyses. RESULTS: Compared to healthy controls, patients with chronic, unexplained fatigue rated themselves as more active before their illness (p < or = 0.001) and less active currently (p < or = 0.001). The patients also reported they currently stood or walked less than the controls (median [inter-quartile range] = 4 2345 versus 9 [7.5-12] hours, p < or = 0.001), and spent more time reclining (median [inter-quartile range] = 12 10111213141516 versus 8 [8-9.5] hours, p < or = 0.001). These differences remained significant for the subset of patients who met strict criteria for chronic fatigue syndrome or fibromyalgia. CONCLUSION: Patients with chronic, unexplained, disabling fatigue reported being more active before becoming ill than healthy controls. This finding could be explained by greater premorbid activity levels that could predispose to illness, or by an overestimation of previous activity. Either possibility could influence patients' perceptions of their current activity levels and their judgments of recovery. Perceived activity should be addressed as part of management of the illness.

Smith WR, Noonan C, Buchwald D. · Department of Psychiatry, University of Washington, Seattle, WA, USA. · Psychol Med. · Pubmed #16893495 No free full text.

Abstract: BACKGROUND: Comprehensive studies of mortality among patients with chronic fatigue (CF) and chronic fatigue syndrome (CFS) have not been published, but several sources suggest that CFS is associated with an elevated risk for suicide. METHOD: Data on 1201 chronically fatigued patients followed in a university-affiliated tertiary-care clinic for up to 14 years were submitted to the Center for Disease Control and Prevention (CDC) National Death Index (NDI) to evaluate all-cause and suicide-caused death rates against standardized mortality rates (SMRs). We used Life Table Analysis to examine the influence of sex and diagnoses of CFS and depression. RESULTS: All-cause mortality in chronically fatigued patients was no higher than expected, but suicide-caused death rates were more than eight times higher than in the US general population. The significant elevation in the SMR of suicide was restricted to those who did not meet criteria for CFS [SMR(CF)=14.2, 95% confidence interval (CI) 5.7-29.3 versus SMR(CFS)=3.6, 95% CI 0.4-12.9]. Among chronically fatigued patients who did not meet CFS criteria, those with a lifetime history of major depression (MD) had higher suicide-caused death rates than among their non-depressed counterparts (SMR(MD)=19.1, 95% CI 7.0-41.5 versus SMR(NMD)=5.6, 95% CI 0.1-31.4), although the difference was not significant. CONCLUSIONS: CFS does not appear to be associated with increased all-cause mortality or suicide rates. Clinicians, however, should carefully evaluate patients with CF for depression and suicidality.

Mease PJ, Clauw DJ, Arnold LM, Goldenberg DL, Witter J, Williams DA, Simon LS, Strand CV, Bramson C, Martin S, Wright TM, Littman B, Wernicke JF, Gendreau RM, Crofford LJ. · Swedish Medical Center, the University of Washington School of Medicine, Seattle, WA, USA. · J Rheumatol. · Pubmed #16265715 No free full text.

Abstract: The objectives of the first OMERACT Fibromyalgia Syndrome (FM) Workshop were to identify and prioritize symptom domains that should be consistently evaluated in FM clinical trials, and to identify aspects of domains and outcome measures that should be part of a concerted research agenda of FM researchers. Such an effort will help standardize and improve the quality of outcomes research in FM. A principal assumption in this workshop has been that there exists a clinical syndrome, generally known as FM, characterized by chronic widespread pain typically associated with fatigue, sleep disturbance, mood disturbance, and other symptoms and signs, and considered to be related to central neuromodulatory dysregulation. FM can be diagnosed using 1990 American College of Rheumatology criteria. In preparation for the workshop a Delphi exercise involving 23 FM researchers was conducted to establish a preliminary prioritization of domains of inquiry. At the OMERACT meeting, the workshop included presentation of the Delphi results; a review of placebo-controlled trials of FM treatment, with a focus on the outcome measures used and their performance; a panel discussion of the key issues in FM trials, from both an investigator and regulatory agency perspective; and a voting process by the workshop attendees. The results of the workshop were presented in the plenary session on the final day of the meeting. A prioritized list of domains of FM to be investigated was thus developed, key issues and controversies in the field were debated, and consensus on a research agenda on outcome measure development was reached.

Turk DC, Robinson JP, Burwinkle T. · Department of Anesthesiology, University of Washington, Seattle, Washington 98195, USA. · J Pain. · Pubmed #15556826 No free full text.

Abstract: Patients with fibromyalgia syndrome (FMS) report pain, fatigue, emotional distress, activity avoidance, and disability. The role of fear of pain and activity in FMS patients has received only limited attention. FMS patients (N = 233) underwent examinations by a physician, physical therapist, and psychologist and completed measures of fear of pain and activity, disability, depressive mood, impact, and pain. Patients with high levels of fear of pain and activity (38.6%) reported greater disability (t = 4.02, P < .001), depressed mood (t = -4.14, P < .001), pain severity (t = -2.71, P < .01), and lower treadmill performance (t = -2.39, P < .05) than patients with low fear. Patients classified on the Multidimensional Pain Inventory as Dysfunctional reported greater fear than Interpersonally Distressed patients and Adaptive Copers (F = 8.13, P < .001). Only 50% of Dysfunctional patients, however, met the criterion of high fear, whereas 23.4% of Adaptive Copers met this criterion. Demographic factors, perceived disability, and Multidimensional Pain Inventory subgroup significantly predicted fear of pain and activity, accounting for 21.2% of the variance. Fear of pain and activity is prevalent among FMS patients. Treatment should address patient fears, because it might reduce disability and rates of nonadherence and attrition from outcome studies. PERSPECTIVE: Fear of movement is a significant concern for chronic pain sufferers because these behaviors maintain pain and increase disability. This study examined the role of fear in FMS, including associations between fear of pain/movement, pain severity, depressed mood, physical performance, and disability in FMS subgroups.

Watson NF, Jacobsen C, Goldberg J, Kapur V, Buchwald D. · Department of Neurology, University of Washington, Seattle 98104-2499, USA. · Sleep. · Pubmed #15453557 No free full text.

Abstract: STUDY OBJECTIVE: To examine the association of chronic fatigue syndrome (CFS) with measures of objective and subjective sleepiness. DESIGN: Monozygotic co-twin control study. SETTING: Academic medical center. PATIENTS AND PARTICIPANTS: Twenty monozygotic twin pairs discordant for CFS. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: All twins completed an Epworth Sleepiness Scale (ESS), 4 Stanford Sleepiness Scales (SSS), and underwent a standard 4-nap multiple sleep latency test. We compared the ESS scores, average SSS scores, and average sleep latency in CFS and healthy twins. The CFS twins reported more sleepiness as measured by mean scores on the ESS (10.9 vs 8.2; 95% confidence interval [CI] = 0.3-5.5; P = .03) and the SSS (3.4 versus 2.1; 95% CI = 0.7-1.9; P < .001). The mean sleep latency on the Multiple Sleep Latency Test was not significantly different between the CFS and healthy twins (8.9 vs 10.0 minutes; 95% CI -4.4-1.7; P = .33). Mean SSS scores increased among the CFS twins and decreased among healthy twins from nap 1 to nap 4 (P < .001). The individual ESS scores and mean sleep latencies on the Multiple Sleep Latency Test were negatively correlated for all the twins (Pearson's r = - 0.40; P = .01), with a slightly stronger association among the healthy twins (Pearson's r = -0.42, P = .07) than the CFS twins (Pearson's r = -0.36, P = .15). CONCLUSIONS: CFS twins reported significantly more subjective sleepiness than their healthy co-twins despite similar nonpathologic mean sleep latencies on the Multiple Sleep Latency Test. Patients with CFS may mistake their chronic disabling fatigue for sleepiness.

Mahurin RK, Claypoole KH, Goldberg JH, Arguelles L, Ashton S, Buchwald D. · Department of Radiology, University of Washington, Seattle, WA 98195-6465, USA. · Neuropsychology. · Pubmed #15099145 No free full text.

Abstract: Twenty-one pairs of monozygotic twins discordant for chronic fatigue syndrome (CFS) and 21 matched healthy control (HC) subjects were assessed with 5 untimed tests and 5 timed tests from the computer-based NeuroCognitive Assessment Battery (R. K. Mahurin, 1993). Random effects regression showed no difference between CFS and healthy twins on any of the cognitive tests. Further, the twin groups did not differ from the HC group on any content-dependent measure. In contrast, both sets of twins performed worse than the HC group on all speed-dependent tests except Finger Tapping. Self-rated fatigue and dysphoric mood were only weakly correlated with cognitive performance. These data point toward a shared genetic trait related to information processing that is manifest in the CFS context. The findings have implications for differentiating genetic and acquired vulnerability in the symptomatic expression of the disorder. ((c) 2004 APA, all rights reserved)

Ball N, Buchwald DS, Schmidt D, Goldberg J, Ashton S, Armitage R. · Virginia Mason Sleep Disorders Center, University of Washington, Seattle, WA, USA. · J Psychosom Res. · Pubmed #15016580 No free full text.

Abstract: PURPOSE: Chronic fatigue syndrome (CFS) is characterized by profound fatigue accompanied by disturbances of sleep, cognition, mood, and other symptoms. Our objective was to describe sleep architecture in CFS-discordant twin pairs. METHODS: We conducted a co-twin control study of 22 pairs of monozygotic twins where one twin met criteria for CFS and the co-twin was healthy. Twins underwent two nights of polysomnography. RESULTS: The percentage of Stage 3 and REM sleep was greater among the CFS twins than their healthy co-twins (P< or = .05 for both), but no other differences in sleep architecture including sleep latency, REM latency, and total sleep time were observed. Compared to their co-twins, CFS twins had higher values for the apnea-hypopnea index and apnea-hypopnea arousal index (P< or =.05 for both). CONCLUSION: These results do not provide strong evidence for a major role for abnormalities in sleep architecture in CFS. Respiration appears impaired in CFS, but these clinical abnormalities cannot alone account for the prominence of sleep complaints in this illness. The co-twin control methodology highlights the importance of selecting well-matched control subjects.

Roy-Byrne P, Smith WR, Goldberg J, Afari N, Buchwald D. · Department of Psychiatry and Behavioral Science, University of Washington, Seattle, WA, USA. · Psychol Med. · Pubmed #14982142 No free full text.

Abstract: BACKGROUND: Fibromyalgia (FM), a chronic pain condition of unknown aetiology often develops following a traumatic event. FM has been associated with post-traumatic stress disorder (PTSD) and major depression disorder (MDD). METHOD: Patients seen in a referral clinic (N=571) were evaluated for FM and chronic fatigue syndrome (CFS) criteria. Patients completed questionnaires, and underwent a physical examination and a structured psychiatric evaluation. Critical components of the diagnostic criteria of FM (tender points and diffuse pain) and CFS (persistent debilitating fatigue and four of eight associated symptoms) were examined for their relationship with PTSD. RESULTS: The prevalence of lifetime PTSD was 20% and lifetime MDD was 42%. Patients who had both tender points and diffuse pain had a higher prevalence of PTSD (OR=3.4, 95% CI 2.0-5.8) compared with those who had neither of these FM criteria. Stratification by MDD and adjustment for sociodemographic factors and chronic fatigue revealed that the association of PTSD with FM criteria was confined to those with MDD. Patients with MDD who met both components of the FM criteria had a three-fold increase in the prevalence of PTSD (95% CI 1.5-7.1); conversely, FM patients without MDD showed no increase in PTSD (OR=1.3, 95% CI 0.5-3.2). The components of the CFS criteria were not significantly associated with PTSD. CONCLUSION: Optimal clinical care for patients with FM should include an assessment of trauma in general, and PTSD in particular. This study highlights the importance of considering co-morbid MDD as an effect modifier in analyses that explore PTSD in patients with FM.

Watson NF, Kapur V, Arguelles LM, Goldberg J, Schmidt DF, Armitage R, Buchwald D. · Department of Neurology and Sleep Disorders Center, University of Washington, Seattle 98104-2499, USA. · Sleep. · Pubmed #12749553 No free full text.

Abstract: STUDY OBJECTIVES: To examine the objective and subjective measures of insomnia in chronic fatigue syndrome (CFS). DESIGN: Monozygotic co-twin control study. SETTING: Academic medical center. PATIENTS OR PARTICIPANTS: Twenty-two pairs of monozygotic twins where 1 member of the pair had CFS and the other did not. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Twenty-two CFS-discordant twin pairs completed a Sleep Disorders Questionnaire, overnight polysomnography, and a postpolysomnography sleep survey. Mean and percent differences in the sleep measures were compared between the CFS and healthy twins using matched-pair methods of analysis. Compared with their healthy co-twins, the CFS twins more frequently endorsed 8 subjective measures of insomnia and poor sleep (all p < or = 0.05). However, the CFS and healthy twins did not differ in objective polysomnographic measures of insomnia, including sleep latency, total sleep time, sleep efficiency, arousal number, arousal index, hypnogram awakenings, rapid eye movement (REM)-sleep latency, and percent stages 1, 2, and 3-4 (delta). Percent stage REM sleep was increased in the CFS twins compared with the healthy twins (27.7% vs. 24.4%, p < or = 0.05). On the postpolysomnography survey, CFS twins reported that they had slept fewer hours (6.2 vs. 6.7; p < or = 0.05), and were less well rested (p < or = 0.001) compared to their co-twins. CONCLUSIONS: CFS patients had worse subjective sleep than their co-twins despite little objective data supporting this discrepancy, suggesting they suffer from an element of sleep-state misperception. The higher percentage of REM sleep in the CFS twins implies that REM sleep may play a role in this illness.

Assefi NP, Coy TV, Uslan D, Smith WR, Buchwald D. · Department of Medicine, University of Washington, Seattle, Washington, USA. · J Rheumatol. · Pubmed #12672203 No free full text.

Abstract: OBJECTIVE: To examine the nature and degree of self-reported disability in patients with chronic fatigue syndrome (CFS) and its associated conditions, fibromyalgia (FM) and subsyndromal fatigue (CF), compared with a chronically fatiguing but unrelated medical condition (MED). METHODS: Six hundred and thirty patients evaluated at the University of Washington Chronic Fatigue Clinic were sent questionnaires asking them to identify the financial, occupational, and personal consequences of their fatiguing illness. Thorough medical evaluations had previously applied accepted criteria for defining CFS, FM, and CF. RESULTS: The FM groups (those with and without CFS) were among the least employed. Likewise, the FM and CFS groups, more frequently than the other groups, endorsed loss of material possessions (such as car), loss of job, and loss of support by friends and family, as well as recreational activities as a result of their fatiguing illness. There were no reliable differences between groups in use of disability benefits. CONCLUSION: There is substantial illness-related disability among those evaluated at a specialized chronic fatigue clinic. Those reporting the most pervasive disability met criteria for FM either alone or in conjunction with CFS. Employers and personal relations of patients with chronic fatigue should make a greater effort to accommodate the illness-related limitations of these conditions, especially for those with FM and CFS.